SIRPα/CD172a Regulates Eosinophil Homeostasis

Abstract

Eosinophils are abundant in the lamina propria of the small intestine, but they rarely show degranulation in situ under steady-state conditions. In this study, using two novel mAbs, we found that intestinal eosinophils constitutively expressed a high level of an inhibitory receptor signal regulatory protein α (SIRPα)/CD172a and a low, but significant, level of a tetraspanin CD63, whose upregulation is closely associated with degranulation. Cross-linking SIRPα/CD172a on the surface of wild-type eosinophils significantly inhibited the release of eosinophil peroxidase induced by the calcium ionophore A23187, whereas this cross-linking effect was not observed in eosinophils isolated from mice expressing a mutated SIRPα/CD172a that lacks most of its cytoplasmic domain (SIRPα Cyto−/−). The SIRPα Cyto−/− eosinophils showed reduced viability, increased CD63 expression, and increased eosinophil peroxidase release with or without A23187 stimulation in vitro. In addition, SIRPα Cyto−/− mice showed increased frequencies of Annexin V-binding eosinophils and free MBP+CD63+ extracellular granules, as well as increased tissue remodeling in the small intestine under steady-state conditions. Mice deficient in CD47, which is a ligand for SIRPα/CD172a, recapitulated these phenomena. Moreover, during Th2-biased inflammation, increased eosinophil cell death and degranulation were obvious in a number of tissues, including the small intestine, in the SIRPα Cyto−/− mice compared with wild-type mice. Collectively, our results indicated that SIRPα/CD172a regulates eosinophil homeostasis, probably by interacting with CD47, with substantial effects on eosinophil survival. Thus, SIRPα/CD172a is a potential therapeutic target for eosinophil-associated diseases.

Mechanism of Siglec-8–mediated cell death in IL-5–activated eosinophils: Role for reactive oxygen species–enhanced MEK/ERK activation

“…For instance, eosinophils are homeostatically present in some tissues with no ill effect, presumably because they are restrained in part by signaling through inhibitory receptors, as was shown for SIRP-α and CD22 in mice. 55, 56 During eosinophilic inflammatory diseases, eosinophils display an activated phenotype and lead to tissue destruction. Homeostatic or inflammatory eosinophils may die silent deaths by either apoptosis or egress from tissue; however, in many diseases, eosinophils have destructive deaths, as outlined above.…”

Roles and Regulation of Gastrointestinal Eosinophils in Immunity and Disease

“…However, phenotypic characterization of murine eosinophils in the intestinal lamina propria has been recently reported by several groups (5, 16, 17). For detection of eosinophils in mice, there are several available markers, including CCR3, sialic acid–binding immunoglobulin-like lectin 7 F (homolog of siglec-8 in humans), and CD125, which encodes for the IL-5 receptor alpha 8 (18–20).…”

“…Thus, a combination of the relative expression of CCR3, Siglec-F, and/or IL-5Rα with their side scatter patterns can be used to delineate eosinophil subsets in the intestine (Fig. 1A) (5, 16, 17). In addition to these markers, intestinal eosinophils of mice express higher levels of myeloid marker CD11b than their blood counterparts and are positive for CD11c, a surface marker used to identify intestinal dendritic cells (Fig.…”

“…In addition, signal regulatory protein α 10 , highly expressed in small-intestinal eosinophils, inhibits degranulation of eosinophils by interaction with their ligand CD47, thus promoting eosinophil survival (Fig. 1A) (16). Also, type 2 innate lymphoid cells 11 have been identified as a specialized cell population supporting the maintenance of murine intestinal eosinophils by secreting IL-5 and IL-13, which promote eosinophil survival and recruitment to the small intestine, respectively, via upregulation of eotaxin (29).…”

“…Although the involvement of intestinal eosinophils in IgA class switching has not yet been directly examined, the impaired IgA production reported in CD47-deficient mice suggests a potential role in IgA synthesis (82). As noted above, small-intestinal eosinophils highly express SIRP-α, a cognate receptor for CD47, and SIRP-α/CD47 signaling contributes to the prolonged survival of murine intestinal eosinophils by regulation of their degranulation (16). The impaired production of IgA in CD47-deficient mice may correlate with reduced viability of small-intestinal eosinophils.…”